This invention relates generally to ethene containing solutions and to the use thereof in methods of therapy or prophylaxis.
The current state of the art in respect of the metabolic role of ethene in mammals is best described in International Agency for Research on Cancer: Monographs of the Evaluation of Carcinogenic Risks to Humans Vol 60, 1994, Ethylene, as published by the World Health Organization. From this reference it may be concluded that ethene has no useful metabolic role in mammals (apart from use as an anaesthetic) and that its production or uptake by mammals seems to be without useful metabolic purpose.
The state of the art was advanced in specification PCT/NZ94/00151 (published as WO 95/17214 and for which the present applicant is an inventor) by the suggestion that ethene production by mammals may be a defense mechanism directed against invading micro-organisms. The use of ethene as a novel sterilizing agent was therefore described therein. Particularly described were sterilizing or micro-organism inhibiting solutions comprising ethene solubilized in a suitable liquid.
It was indicated that the solutions of WO 95/17214, would have utility in prophylaxis and/or therapy through a direct antimicrobial effect on infective or disease causing agents.
The application has now identified a disadvantage associated with the use of the solutions of WO 95/17214. These solutions have been found to exhibit poor storage and chemical stability. This lack of stability is believed to result from ethene""s ability to react with other components in solutions.
More specifically, the applicant has found that ethene may react with other components in a liquid resulting in one or more of, a reduction in the amount of ethene in solution, alteration in the pH of the solution or the production of undesirable reaction products. The applicant has surprisingly found that ethene in solution may be reduced by 50% for example by reaction with such components. The applicant has found such reactions entirely unanticipated and at variance with the disclosure of WO 95/17214.
These components may comprise ions, for example H+ and OHxe2x88x92 ions, calcium ions, or other impurities such as microscopic plant matter, calcium solids, or entrained gases, for example, air, oxygen or chlorine.
While not bound by the following, it is suggested for example, that one reaction may be between hydroxy ions and ethene forming 2-hydroxy ethene. Similarly, oxygen entrained in an ethene containing solution may also react with ultra violet light, or even neon light to produce ozone which subsequently reacts with ethene to produce ethylene oxide. The presence of a carcinogen such as ethylene oxide greatly reduces the utility of the ethene containing liquid for consumption. Moreover, all of these reactions may reduce the amount of ethene solubilized in the liquid.
By way of example, the applicant has found that ethene added to a suitable liquid, in this case water of a potable standard containing components giving a conductivity of 148 micromhos (reciprocal megohms) per centimetre, reacted to give a rise in pH which may continue over days and months of storage. A similar reaction was not observed when the water used was deionised by distillation to substantially zero conductivity prior to the addition of ethene.
A lack of storage stability is particularly disadvantageous for this ethene product if it is to be involved in lengthy transport operations, or where an extended shelf life is desirable.
As noted above, the applicant has now surprisingly found that an ethene containing solution exhibiting usefully increased chemical and storage stability can be produced by solubilizing ethene in a reactivity reduced liquid. The solution produced is useful as a tonic.
It is therefore an object of the invention to provide a storage stable solution comprising ethene solubilized in a suitable liquid or at least to provide the public with a useful choice.
It is a further object of the invention to provide methods of prophylaxis and/or therapy in which the storage stable solution is used as a directly active antimicrobial agent, or again at least to provide the public with a useful choice.
It was also the applicant""s expectation that the solutions of WO 95/17214 would have utility in prophylaxis and/or therapy through a direct antimicrobial effect on infective or disease causing agents. However, the applicant has found that ethene containing solutions may not have a direct sterilizing/inhibiting effect against a number of micro-organisms in vitro. Some examples of micro-organisms found by the applicant not to be sterilized in vitro by solubilized ethene are: Influenza A (H3N2), Poliovirus type 1 (Sabin) and Herpes simplex virus. In addition to these viruses, eight bacterial strains representing four bacterial genera (Staphylococcus, Pseudomonas, Klebsiella, Enterococcus) of important human pathogens were tested in vitro without apparent sterilizing success.
The applicant has surprisingly found that, notwithstanding the apparent lack of an in vitro antimicrobial efficacy of ethene on certain micro-organisms, ethene, more particularly solubilized ethene, may provide prophylactic and/or therapeutic effects in vivo in hosts to which the ethene is administered. This is even against a micro-organism such as Herpes simplex which ethene does not inhibit or sterilize in vitro. In other words, an ethene induced micro-organism sterilizing/inhibiting effect may be observed in a host, even though the micro-organism(s) within that host may not be directly ethene labile. In this respect the applicant has found that a useful metabolic role of ethene in man is the same as its useful metabolic role in plants, that of a primary immunogen. It is upon this entirely unexpected finding that this invention is also partly based.
It is therefore a further object of the invention to provide methods of prophylaxis and/or therapy in which ethene is used otherwise than as a directly active antimicrobial agent, or at least to provide the public with a useful choice.
In a first aspect, the present invention can be said to broadly consist in a storage stable solution comprising ethene solubilized in a suitable liquid. The storage stable solution is preferably a tonic solution comprising ethene solubilized in a reactivity reduced liquid.
Desirably, the liquid is purified. Most preferably, the liquid is a deionized liquid.
In a general aspect, the present invention provides a method for improving metabolic function in a host which method involves administering to the host an effective amount of a storage stable solution of the invention.
In a further aspect, the present invention provides a method for prophylaxis and/or therapy for the treatment of diseases or infections in a host by exerting a direct antimicrobial effect, and which involves the step of administering to the host an effective amount of a storage stable solution of the invention.
In a related aspect, the present invention provides the use of a storage stable solution of the invention in the preparation of a medicament for use in prophylaxis and/or therapy against microbial infection, whereby the medicament exerts a direct antimicrobial effect.
In a still further aspect, the present invention can be said to broadly consist in a method for prophylaxis and/or therapy for the treatment of diseases or infections in a host other than through exerting a direct antimicrobial effect and which involves the step of administering to the host an effective amount of ethene.
More generally, the invention provides a method of improving metabolic function in a host which method involves the step of administering to the host an effective amount of ethene, and provided that the improved metabolic function is achieved other than through exerting a direct antimicrobial effect
In a further aspect, the present invention provides a method of priming and/or causing a host to mount a protective response, more particularly a protective immune response, against disease or infective micro-organisms and which involves the step of administering to the host an effective amount of ethene.
In a still further aspect, the invention provides a method of administering ethene to a host wherein the ethene provides an indirect sterilizing or micro-organism inhibiting effect, such effect being prophylactic and/or therapeutic and such effect being caused by host systemic factors, for example, T-lymphocytes, or leukocytes potentiated in the host by the administration of ethene.
In still a further aspect, the present invention may provide a method of therapy and/or prophylaxis against microbial infection in a host which comprises the steps of:
(a) administering an effective amount of ethene to said host to potentiated and/or prime the immune system of the host to generate a host protective immune response against said microbial infection; and
(b) administering an amount of an active agent which has a direct antimicrobial effect sufficient to sterilize or at least inhibit the micro-organism.
In the context of this application, the host is preferably human but may be animal.
In one preferred embodiment of the indirect acting methods of the invention, the immune response induced by the administration of ethene is a humoral response.
Conveniently, the administration of ethene causes the production of systemic factors, for example in cases of HIV infection, cells involved in mounting a humoral immune response to be increased.
Most conveniently and by way of example, the administration of ethene may cause the population of CD4 T-lymphocytes to increase, remain stable or decrease at a slower rate than would otherwise be the case without the administration of ethene.
The host protective response engendered through the administration of ethene may also be a healing effect in damaged tissue of the host involved in mounting an immune response, for example liver tissue or lymphatic tissue, and thus enable such tissues to function to better general, metabolic and immunological effect.
In a particularly preferred but not limiting embodiment of the indirect methods, the micro-organism against which the therapeutic effect is to be mounted is HIV. The therapeutic effect may be directed at other micro-organisms as well for example, Herpes simplex, or micro-organisms involved in Hepatitis or Glandular fever infection. More preferably, but not essentially, the therapeutic administration of ethene may be in combination or conjunction with other antimicrobial substances, for example Zidovudine (AZT), or antibiotics such as Penicillin.
In the methods of the invention where ethene is required to be administered for indirect effects it is conveniently provided in the form of a composition containing ethene solubilized in a suitable liquid such as water. Most desirably, ethene is more suitably administered in the form of the storage stable solution of the invention.
In another aspect, the present invention provides the use of ethene in the preparation of a medicament for use in prophylaxis and/or therapy against microbial infection, whereby the medicament induces an indirect antimicrobial effect through an ability to prime and/or cause the host to mount a protective response, particularly a protective immune response, against infection.
The invention is precedingly broadly defined. However, those persons skilled in this art will appreciate that the invention is not limited to only those aspects defined but that it also includes embodiments for which the following description provides examples.